Acetaminophen-Induced Hepatotoxicity in Mice Occurs with Inhibition of Activity and Nitration of Mitochondrial Manganese Superoxide Dismutase
Open accessAbstract
In overdose the analgesic/antipyretic acetaminophen (APAP) is hepatotoxic. Toxicity is mediated by initial hepatic metabolism to N-acetyl-p-benzoquinone imine (NAPQI). After low doses NAPQI is efficiently detoxified by GSH. However, in overdose GSH is depleted, NAPQI covalently binds to proteins as APAP adducts, and oxygen/nitrogen stress occurs. Toxicity is believed to occur by mitochondrial dysfunction. Manganese superoxide dismutase (MnSOD) inactivation by protein nitration has been reported to occur during other oxidant stress-mediated diseases. MnSOD is a critical mitochondrial antioxidant enzyme that prevents peroxynitrite formation within the mitochondria. To examine the role of MnSOD in APAP toxicity, mice were treated with 300 mg/kg APAP. GSH was significantly reduced by 65% at 0.5 h and remained reduced from 1 to 4 h. Serum alanine aminotransferase did not significantly increase until 4 h and was 2290 IU/liter at 6 h. MnSOD activity was significantly reduced by 50% at 1 and 2 h. At 1 h, GSH was significantly depleted by 62 and 80% at nontoxic doses of 50 and 100 mg/kg, respectively. No further GSH depletion occurred with hepatotoxic doses of 200 and 300 mg/kg APAP. A dose response decrease in MnSOD activity was observed for APAP at 100, 200, and 300 mg/kg. Immunoprecipitation of MnSOD from livers of APAP-treated mice followed by Western blot analysis revealed nitrated MnSOD. APAP-MnSOD adducts were not detected. Treatment of recombinant MnSOD with NAPQI did not produce APAP protein adducts. The data indicate that MnSOD inactivation by nitration is an early event in APAP-induced hepatic toxicity.
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Toxic doses of paracetamol inhibit manganese superoxide dismutase in animal studies.
“Toxic doses of paracetamol inhibit manganese superoxide dismutase in animal studies [118].”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [118]
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- Authors
- Agarwal, R., MacMillan-Crow, L. A., Rafferty, T. M., Saba, H., Roberts, D. W., Fifer, E. K., James, L. P., & Hinson, J. A.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- Venue
- The Journal of Pharmacology and Experimental Therapeutics
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 337
- Issue
- 1
- Pages
- 110-116
- ISSN
- 0022-3565 (ISSN-L)
- PMC
- PMC3063736
- OpenAlex
- W2103891066
- Cited by
- 116
- References
- 41
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 8 · 2016: 8 · 2015: 11 · 2014: 12 · 2013: 13 · 2012: 11
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Pharmacology and Experimental Therapeutics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Arkansas Biosciences Institute
- National Institutes of Health (5r01dk079008-05)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK059872, R01-DK079008, R01DK075936, R01-DK75936)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Surgery › Paraquat toxicity studies and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- acetaminophen hepatotoxicity, manganese superoxide dismutase, protein nitration, N-acetyl-p-benzoquinone imine, glutathione depletion, mitochondrial dysfunction, peroxynitrite, oxidative stress, dose-dependent toxicity, acetaminophen overdose
- MeSH terms
- Acetaminophen, Animals, Dose-Response Relationship, Drug, Enzyme Inhibitors, Male, Mice, Inbred C57BL, Mitochondria, Liver, Nitrates, Superoxide Dismutase, Oxidative Stress, Mice, Chemical and Drug Induced Liver Injury
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